Leonard Mayer, Ph.D.Chief, Meningitis Laboratory

MVPDB, DBD, CDC

Characterization of candidate vaccine antigens among

invasive Neisseria meningitidis isolates in the

United States

National Center for Immunization & Respiratory DiseasesMeningitis and Vaccine Preventable Diseases Branch

OutlineØ IntroductionØ Active Bacterial Core surveillance and the

meningococcal strain collection in the USØ Prevalence and genetic diversity of vaccine

antigen FHbp, NadA and NhbA in the USØ Epidemiological features of the three

vaccine antigens in the USØ Molecular epidemiological features of the

US meningococcal isolatesØ Relationship between clonal complex and

vaccine antigens Ø Summary

Importance of Serogroup B Vaccines in the US

Ø Serogroup B cause of 1/3 of diseaseØ >60% of disease in infants age <1 yearØ Proportion will increase with MenACWY vaccine program

Ø Overall meningococcal disease incidence lowØ Vaccines would have to cover large proportion of disease causing strains to have impact

Ø Only adolescents receive MenACWY at this timeØ Benefits of serogroup B vaccination program increases if vaccine provides protection against other serogroupsØ Duration of protection important as cases do occur throughout life

Candidate Serogroup B Vaccines

Bivalent vaccine FHbp (factor H binding protein)-subfamily B (variant 1)-subfamily A (variant 2 & 3)

Multi-component vaccine FHbp variant 1 (subfamily B)

NadA (Neisserial adhesin A )NhbA (Neisserial heparin binding antigen ) (5 gene products with fusions 2 + 2 + 1 => 3 peptides)OMV NZ (Outer membrane vesicles of the New Zealand epidemic strain)

Active Bacterial Core surveillance (ABCs) Sites*

ABCs

*Represents approximately 13% of US population (40 million population size)

Meningococcal Disease Incidence, United States, 1999-2008

0

0.2

0.4

0.6

0.8

1

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Rat

e pe

r 100

,000

B C Y Total

Active Bacterial Core surveillance system, incidence excluding Oregon estimated to U.S. population of 49 states and Oregon incidence added in for 50 state estimate

Annual Average Serogroup B Incidence, by Age, 1999-2008

0

0.5

1

1.5

2

2.5

3

3.5

Rat

e pe

r 100

,000

Age (years)

Active Bacterial Core surveillance system, incidence excluding Oregon estimated to U.S. population of 49 states and Oregon incidence added in for 50 state estimate

Meningococcal Disease Incidence ABCs*, 2000-2008

All serogroups Serogroup BCalifornia 0.71 0.28

Colorado 0.47 0.15

Connecticut 0.34 0.08

Georgia 0.30 0.11

Maryland 0.36 0.11

Minnesota 0.48 0.14

New York 0.57 0.15

Oregon 1.34 0.83

Tennessee 0.49 0.18

US Incidence (estimated from ABCs)

0.44 0.15

*Analysis excludes New Mexico which joined ABCs in 2004

Serogroup B Isolates Collected, ABCs, 2000-2008

*Joined ABCs 7/1/2000

Isolates % of Total Isolates

Person Years % of Total Population

California 76 11.7 29,091,969 8.7

Colorado* 21 3.2 19,116,641* 5.7

Connecticut 25 3.9 31,189,196 9.4

Georgia 85 13.1 80,497,698 24.1

Maryland 51 7.9 49,589,741 14.9

Minnesota 63 9.7 45,708,268 13.7

New York 26 4.0 19,108,891 5.7

Oregon 258 39.7 32,376,181 9.7

Tennessee 45 6.9 26,739,506 8.0

Total 650 100 333,418,091

Weighted Isolates, ABCs, Serogroup B, 2000-2008

Isolates % of Total Isolates

Person Years % of Total Population

California 62 16.9 29,091,969 8.7Colorado* 17 4.7 19,116,641 5.7Connecticut 21 5.6 31,189,196 9.4Georgia 70 18.9 80,497,698 24.1Maryland 42 11.4 49,589,741 14.9Minnesota 52 14.0 45,708,268 13.7New York 21 5.8 19,108,891 5.7Oregon 46 12.6 32,376,181 9.7Tennessee 37 10.0 26,739,506 8.0Total 368 333,418,091

*Joined ABCs 7/1/2000

Prevalence and genetic diversity of FHbp, NadA, and NhbA

Isolates Characterized for Vaccine Antigens, ABCs

Antigen Serogroup Years* Tested

FHbp and NadA presence (PCR+)

B 2000-2008**

650

NhbA B 2000-2008 136

FHbp, NadA presence, and NhbA

C 2006-2008 114

FHbp, NadA presence, and NhbA

Y 2006-2008 119

*Random sample of serogroup B isolates from 1989-1999 also tested, data not presented**650 NmB isolates, 2000-8 (with weighting for Oregon)

FHbp Subfamily/Variant by Serogroup

*650 NmB isolates, 2000-8 (with weighting for Oregon)**11 serogroup C isolates contain a single nucleotide deletion creating a frame-shift

Proportion of nadA PCR+ and nhbA+ Isolates by Serogroup

*650 NmB isolates, 2000-8 (with weighting for Oregon); 514 isolates not tested for nhbA

NadA Presence Among Nm Isolates by FHbp Subfamily/Variant

Serogroup Years* FHbp subfamily/variant

% nadA PCR+

B 2000-2008*

B/v1 60%

A/v2-3 9%

C 2006-2008 B/v1 68%

A/v2-3 52%

Y 2006-2008 B/v1 0

A/v2-3 4%

*650 NmB isolates, 2000-8 (with weighting for Oregon)

FHbp Subvariant by Serogroup

B (n=650) C (n=103) Y (n=119)0%

20%

40%

60%

80%

100% Other*3.61/A013.31/A472.25/A152.24/A122.22/A102.21/A072.19/A222.16/A19

Serogroup

650 NmB isolates, 2000-8 (with weighting for Oregon); *Subvariants that were present in >5 isolates of any serogroup (B, C, or Y) are shown. Other includes subvariants present in ≤5 isolates of any serogroup (B, C, or Y).

B (n=34) C (n=40) Y (n=4)0%

20%

40%

60%

80%

100% NadA-1.73NadA-3.53Na-dA2.46NadA-1.39Na-dA2.33NadA-3.8

Serogroup

NadA Subvariant by Serogroup

Not weighted for Oregon; all subvariants that were present in any serogroup (B, C, or Y) are shown. 

B( n=136) C (n=111) Y (n=114)0%

20%

40%

60%

80%

100% Other*29212013109875321Serogroup

NhbA Subvariant by Serogroup

650 NmB isolates, 2000-8 (with weighting for Oregon); *Subvariants that were present in >5 isolates of any serogroup (B, C, or Y) are shown.  Other includes subvariants present in ≤5 isolates of any serogroup (B, C, or Y).

Epidemiological features of the three vaccine antigens in NmB isolates

2000 2001 20022003 20042005 2006 2007200805

10152025303540 v1/B v2-3/A

Num

ber

FHbp Subfamily/Variant Distribution Among NmB

Isolates by Year

650 NmB isolates, 2000-8 (with weighting for Oregon)

Distribution of Most Frequent FHbp Subvariants Among NmB

Isolates by Year

650 NmB isolates, 2000-8 (with weighting for Oregon); *Subvariants that were present in ≥25 NmB isolates are shown.  Other includes subvariants present in <25 NmB isolates.

FHbp Subfamily/Variant Distribution Among NmB

Isolates by Age-Group

650 NmB isolates, 2000-8 (with weighting for Oregon)

FHbp Subfamily/Variant Distribution Among NmB

Isolates by Syndrome

650 NmB isolates, 2000-8 (with weighting for Oregon)

FHbp Subfamily/Variant Distribution Among NmB

Isolates by State

Not weighted for Oregon

Molecular epidemiological features of the U.S. meningococcal isolates

Most Frequent Clonal Complexes and the Serogroup Typically

Associated With ItCC Serogroup

ST-32 BST-41/44 B

ST-23 YST-11 C

ST-162 BST-35 B

ST-103 C

Most Frequent NmB Clonal Complexes by Syndrome

650 NmB isolates, 2000-8 (with weighting for Oregon); *CC that were present in ≥25 NmB isolates are shown.  Other includes CC present in <25 NmB isolates.

Most Frequent NmB Clonal Complexes by Age-Group

650 NmB isolates, 2000-8 (with weighting for Oregon); *CC that were present in ≥25 NmB isolates are shown.  Other includes CC present in <25 NmB isolates.

Most Frequent NmB Clonal Complexes by State

Not weighted for Oregon; *CC that were present in ≥25 NmB isolates are shown.  Other includes CC present in <25 NmB isolates.

Most Frequent NmB Clonal Complexes by Year

650 NmB isolates, 2000-8 (with weighting for Oregon); *CC that were present in ≥25 NmB isolates are shown.  Other includes CC present in <25 NmB isolates.

Most Frequent PorA Types by Serogroup

650 NmB isolates, 2000-8 (with weighting for Oregon); *PorA types that were present in ≥18 isolates in any serogroup (B, C, or Y) are shown.  Other includes PorA types present in <18 isolates in any serogroup (B, C, or Y) .

Most Frequent PorA Types by Syndrome Among NmB Isolates

650 NmB isolates, 2000-8 (with weighting for Oregon); *PorA types that were present in ≥30 NmB isolates are shown.  Other includes PorA types present in <30 NmB isolates.

Most Frequent PorA Types by Age-Group Among NmB Isolates

650 NmB isolates, 2000-8 (with weighting for Oregon); *PorA types that were present in ≥30 NmB isolates are shown.  Other includes PorA types present in <30 NmB isolates.

Most Frequent PorA Types by State Among NmB Isolates

Not weighted for Oregon; *PorA types that were present in ≥30 NmB isolates are shown.  Other includes PorA types present in <30 NmB isolates.

Most Frequent PorA Types by Year Among NmB Isolates

650 NmB isolates, 2000-8 (with weighting for Oregon); *PorA types that were present in ≥30 NmB isolates are shown.  Other includes PorA types present in <30 NmB isolates.

Relationships between clonal complex and vaccine antigens

FHbp Subvariant by Clonal Complex Among NmB Isolates

650 NmB isolates, 2000-8 (with weighting for Oregon); *Subvariants that were present in ≥25 NmB isolates are shown.  Other includes subvariants present in <25 NmB isolates; **CC that were present in ≥25 NmB isolates are shown.  Other includes CC present in <25 NmB isolates.

Proportion of NmB Isolates with NadA Presence by Clonal Complex

650 NmB isolates, 2000-8 (with weighting for Oregon); *CC that were present in ≥25 NmB isolates are shown.  Other includes CC present in <25 NmB isolates.

NhbA Subvariant by Clonal Complex in NmB Isolates

Not weighted for Oregon; 514 isolates not tested for nhbA; *Subvariants that were present in ≥10 NmB isolates are shown.  Other includes subvariants present in <10 NmB isolates; **CC that were present in ≥25 NmB isolates are shown.  Other includes CC present in <25 NmB isolates.

SummaryØ FHbp and NhbA are widely distributed

among NmB and non-B Nm isolates. All isolates contain one of these two antigens.

Ø NadA is only present in a small subset of Nm isolates.

Ø Proportion of strains with FHbp B/v1 vary by geographic area and age groupØ Oregon with high B/v1 rates because of

the outbreak cloneØ Young children and elderly more likely to

have an A/2-3 strain

Summary

Ø Distribution of the major clonal complexes among the US isolates is relatively stable over time.

Ø PorA in the US isolates is considerably diverse, but composition of the major PorA types did not show significant variation over time

Ø Some association was observed between clonal complex and these vaccine antigens but clonal complex cannot be used to predict vaccine antigen type.

Implications for a serogroup B vaccination program in the U.S.

Ø Potential for broad protection against serogroup B and non-B strains

Ø Data needed regarding antigen expression and their ability to induce sufficient serum bactericidal activity against the US isolates.

Acknowledgements

The MVPDB Epidemiology TeamThe Meningitis LaboratoryNovartis VaccinesPfizer Vaccine ResearchUniversity of PittsburgABCs Team

Thank you

National Center for Immunization & Respiratory DiseasesMeningitis and Vaccine Preventable Diseases Branch

NmB Weighting for Oregon

• To better estimate the prevalence of vaccine antigens on NmB strains circulating in the US, analyses of NmB isolates are weighted to account for the increased incidence of NmB in Oregon– A weight of 0.10 was assigned to isolates

from Oregon– A weight of 0.90 (1-0.10) was assigned to

isolates from other ABCs sites• All results presented for NmB will be

weighted for Oregon, unless specified